Acute attacks of migraine are usually treated with a peripheral vasoconstrictor, such as ergotamine, which may be co-administered with caffeine, and dihydroergotamine; an antipyretic analgesic, such as acetylsalicylic acid or p-acetylaminophenol; and/or an anti-emetic such as cyclizine, metoclopramide and thiethylperazine. It has also been reported (J. B. Hughes, Med. J. Aust. 2, No. 17, 580, 1977) that immediate relief of acute migraine attack can be obtained by the slow intravenous injection of metoclopramide (10 mg).
It is believed that 5-hydroxytryptamine or serotonin (5-HT) is the naturally occurring substance most likely to play a role in the pathophysiology of migraine. Increased amounts of 5-HT and its metabolite 5-hydroxyindoleacetic acid are excreted in the urine during most attacks. Further, plasma and platelet 5-HT concentrations rapidly fall at the onset of an attack and remain low while the headache persists. Moreover, attacks of migraine have been clearly associated with periods of thrombocytopaenia in certain patients. It has been proposed that compounds which block the activity of 5-HT would be of use in the treatment of migraine (J. R. Fozard, International Headache Congress 1980, reported in Advances in Neurology, Vol. 33, Raven Press, N.Y., 1982).
The known migraine prophylactic drugs, methysergide, propanolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but are all 5-HT D-receptor antagonists at the doses used clinically for the treatment of migraine. Metoclopramide is a potent 5-HT M-receptor antagonist and it has been proposed (J. R. Fozard supra) that a blockade of the M-receptor present on afferent sensory neurones affords symptomatic relief in an acute migraine attack.
It is an object of the present invention to provide compounds which are more potent and selective 5-HT M-receptor antagonists than metoclopramide and which can be useful for the treatment of migraine.
The potency as 5-HT M-receptor antagonists of (-) cocaine and some related compounds has been reported (J. R. Fozard et al, Eur. J. Pharmacol., 59, 1979, 195-210). However, with the exceptions of nor(-)cocaine and benzoyltropine, none are as potent as metoclopramide. The pA.sub.2 values reported for nor(-) cocaine and benzoyltropine are 7.7 and 7.12 respectively, while the pA.sub.2 5-HT value determined for metoclopramide by the same procedure is 7.2. (J. R. Fozard et al, Eur. J. Pharmacol., 49, 1978, 109-112).
Surprisingly, it has been found that di- or tri-substitution of benzoyltropine by alkyl, alkoxy or halogen in the 3,4 or 3,5 or 3,4,5 positions of the benzene ring substantially enhances the potency of benzoyltropine as a 5-HT M-receptor antagonist.
The following tropyl benzoate derivatives are known compounds.
TABLE I ______________________________________ KNOWN TROPYLBENZOATES OF FORMULA I R.sub.1 R.sub.2 R.sub.3 Reference ______________________________________ OCH.sub.3 H H C.A. 59, 5665 OCH.sub.3 OCH.sub.3 OCH.sub.3 OCH.sub.3 OCH.sub.3 OC.sub.4 H.sub.9 C.A. 67, 53963 Cl H H C.A. 78, 119197 Cl Cl H OCH.sub.3 H OCH.sub.3 C.A. 28, 5596.sup.9 CH.sub.3 CH.sub.3 H UK Patent 1,012,622 ______________________________________
Some of these known tropyl benzoate derivatives and certain known positional isomers thereof have been reported to have pharmacological activity, specifically local anesthetic, central nervous system stimulant, cholinolytic and/or spasmolytic activity. However no pharmacological activity indicating their use for the treatment of migraine has been reported.
The compounds of formula (I) below can be effectively administered in the treatment of migraine at dose levels well below those at which pharmacological activity has previously been reported for any of the said known compounds or their known isomers.